1. Field of the Invention
The present invention relates to epipodophyllotoxin glucoside derivatives, to their use as tumor-inhibiting substances, to pharmaceutical compositions containing the novel compounds, and to intermediates for their preparation. More particularly, the novel antitumor compounds are lactam analogs of epipodophyllotoxin glucosides.
2. Background Art
Etoposide (Ia) and teniposide (Ib) are clinically useful anticancer agents derived from the naturally occurring lignan, podophyllotoxin. Currently etoposide is marketed in the United States under the trade name Vepesid for the treatment of small cell lung cancer and testicular cancer. ##STR1##
Podophyllotoxin and its derivatives have a highly strained trans-fused lactone ring in which the .alpha.-carbon is particularly prone to base-induced epimerization to give the thermodynamically more stable cis-fused lactone (picro form). The picro compounds have greatly diminished biological activities compared to the parent compounds. In vivo, etoposide is extensively metabolized to the open ring hydroxy acid. Thus an object of the present invention is to provide antitumor derivatives of epipodophyllotoxin glucoside which are more resistant to epimerization and/or less susceptible to deactivation by ring opening in vivo.
Epipodophyllotoxin glucosides and the methods for their preparation are disclosed in U.S. Pat. No. 3,408,441 awarded to Wartburg et al and U.S. Pat. No. 3,524,844 to Keller-Juslen et al. These compounds, in particular etoposide, serve as starting materials for our synthesis of compounds of the present invention.
U.S. Pat. No. 2,977,359 discloses the ring opening of podophyllotoxin with hydrazine to provide selectively either the cis-hydrazide (IIa) or the trans-hydrazide (IIb), the stereospecific reduction of the hydrazides to the corresponding hydroxy amides (IIIa and IIIb) using Raney nickel in ethanol, and the reaction of the hydrazides with aldehydes or ketones to provide the corresponding hydrazones (IVa and IVb). Although the amides and hydrazones are said to have anti-mitotic activity, no data showing such property are given in the patent specification. ##STR2##
The use of substituted hydrazines in this ring opening reaction has also been reported (Helv. Chim. Acta, 1959, 42:890-907). The ethyl hydrazide of podophyllotoxin (V) underwent clinical trials but showed minimal antitumor activity (Cancer Chemoth. Rep., 1966, 50:565-571). ##STR3##
Also reported in the Helv. Chim. Acta paper, supra. are the hydrazides of 4'-demethylpodophyllotoxin and epipodophyllotoxin.
The preparation of the lactam of .beta.-apopicropodophyllin (VI) from .beta.-apopicropodophyllin and ammonia is described in Indian J. Chem., 1987, 26B: 131-5. ##STR4##